期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 24, 期 6, 页码 1068-1076出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.0c00088
关键词
asymmetric synthesis; ethyl (S)-4-chloro-3-hydroxybutanoate; alcohol dehydrogenases; high substrate and product tolerance; monophasic aqueous system
资金
- National Natural Science Foundation of China [21776084, 21606062]
- Fundamental Research Funds for the Central Universities [22221818014]
Bioreductions catalyzed by alcohol dehydrogenases (ADHs) play an important role in the synthesis of chiral alcohols. However, the synthesis of ethyl (S)-4-chloro-3-hydroxybutyrate [(S)-CHBE], an important drug intermediate, has significant challenges concerning high substrate or product inhibition toward ADHs, which complicates its production. Herein, we evaluated a novel ADH, SmADH31, obtained from the Stenotrophomonas maltophilia genome, which can tolerate extremely high concentrations (6 M) of both substrate and product. The coexpression of SmADH31 and glucose dehydrogenase from Bacillus subtilis in Escherichia coli meant that as much as 660 g L-1 (4.0 M) ethyl 4-chloroacetoacetate was completely converted into (S)-CHBE in a monophasic aqueous system with a >99.9% ee value and a high space-time yield (2664 g L-1 d(-1)). Molecular dynamics simulation shed light on the high activity and stereoselectivity of SmADH31. Moreover, five other optically pure chiral alcohols were synthesized at high concentrations (100-462 g L-1) as a result of the broad substrate spectrum of SmADH31. All these compounds act as important drug intermediates, demonstrating the industrial potential of SmADH31-mediated bioreductions.
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